A.Camphorquinone oxime. A flame-dried 1-L three-necked, round-bottomed flask equipped with a mechanical stirrer, a thermometer and septum is charged with potassium t-butoxide (46.0 g, 410 mmol)(Note 1). The contents of the flask are thoroughly purged with a stream of N2 exhausted through an oil bubbler. After 15 min, 500 mL of Et2O(Note 2) is added via cannula and the flask is submerged in a cold bath cooled to −30°C (Note 3). A second 250-mL round-bottom flask is charged with (R)-Camphor (50.0 g, 328 mmol)(Note 4) and 100 mL of Et2O. The resulting clear solution is added via cannula into the first flask over 10 min while keeping the internal temperature below −30°C. The second flask is thoroughly rinsed with 20 mL of Et2O, which is also transferred into the first flask. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature. After stirring at room temperature for 30 min, the reaction mixture is cooled to −30°C. Isoamyl nitrite (55.0 mL, 409 mmol)(Note 5) is added by syringe over 20 min while keeping the internal temperature below −30°C. An orange to red color appears during the addition of isoamyl nitrite. The reaction mixture is allowed to warm to room temperature and is stirred for 16 hours at ambient temperature under a N2 atmosphere. The solution is extracted with water (3 × 150 mL), and the combined aqueous layers (approximately 450 mL) are cooled in an ice bath with magnetic stirring. The pH is adjusted to 4 by dropwise addition of approximately 30 mL of conc. HCl. After the pH is adjusted, an off-white solid precipitates from solution. The biphasic mixture is extracted with CH2Cl2 (3 × 150 mL). The combined organic layers are washed successively with 50 mL of saturated NaHCO3, 50 mL of water, 50 mL of brine, and then dried over anhydrous MgSO4. The solvent is removed in vacuo to afford 52.8 g (89%) of the title compound. The solid is a 10/90 mixture of syn- and anti-camphorquinone oximes (Note 6). This material is suitable for the next reaction without further purification.

B.(2S)-(−)-3-exo-Aminoisoborneol. A 250-mL two-necked, round-bottomed flask is charged with camphorquinone oximes (12.1 g, 66.8 mmol). The flask is fitted with a condenser and a septum, and is thoroughly purged with a steady stream of N2. After 15 min, the N2 flow is reduced to a slow bleed and 30 mL of anhydrous THF(Note 2) is added via syringe. The homogeneous solution is cooled in an ice bath to 0°C. A 1.0 M solution of LiAlH4 in THF (100 mL, 100 mmol)(Note 7) is slowly transferred via cannula to the mixture over 30 min (Note 8). After vigorous H2 gas evolution ceased, the reaction mixture is allowed to warm to ambient temperature and then heated at reflux for 30 min. The solution is cooled to room temperature, diluted with 65 mL of Et2O, cooled to 0°C and quenched by the successive dropwise addition of 3.8 mL of water, 3.8 mL of 10% NaOH solution, and 11.4 mL of water (Note 9). The colorless precipitate was vacuum filtered through Celite, and the filter cake was washed with THF (3 × 20 mL)(Note 10). The combined filtrate was concentrated to give 10.4 g (92%) of a waxy solid. This material was used in the next step without further purification.

C.(2S)-(−)-exo-(Morpholino)isoborneol. To a 150-mL round-bottomed flask charged with (2S)-(−)-3-exo-aminoisoborneol (6.53 g, 38.6 mmol) is added 40 mL of reagent grade DMSO followed by Et3N (16.3 mL, 117 mmol)(Note 11). Bis(2-bromoethyl) ether (6.50 mL, 46.5 mmol)(Note 11) in 30 mL of DMSO is added dropwise over 10 min and the reaction mixture is stirred at ambient temperature under N2 for 72 hours. The solution is poured into 400 mL of water, and the aqueous mixture is extracted with Et2O (3 × 150 mL). The combined organic layers are washed successively with 100 mL of water, 50 mL of brine and then dried over anhydrous MgSO4. The solvent is removed in vacuo and the residue is purified by flash column chromatography (Notes 12, 13 and 14) to give 5.23 g (57%) of (−)-MIB as a colorless solid.

2. Notes

1.
Potassium t-butoxide was purchased from Acros and used under a stream of N2.

2.
Et2O and THF were purchased from Fisher and dried by passage through an activated alumina column under N2.

3.
The reaction was successfully performed at temperatures ranging from −30°C to −50°C.

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

(−)-MIB has been shown to be an excellent chiral ligand in the asymmetric alkylation of aldehydes. In comparison, MIB was equal or better than DAIB in Et2Zn addition to aromatic aldehydes with ee's > 95. Highly enantioselective Et2Zn additions to alkyl substituted aldehydes are also possible with (−)-MIB.5 Remarkably, the generation of (S)-1-phenylpropan-1-ol with 90% ee can be achieved when MIB of only 10% ee was used in the Et2Zn addition with benzaldehyde. This result shows a large positive non-linear effect that parallels DAIB.6 Recently, MIB has been shown to be equally effective with DAIB in the alkenylzinc addition to aldehydes pioneered by Oppolzer.7 A number of terminal alkynes with various substituents were used in the study. Using MIB in this reaction constitutes a powerful and practical method to access both enantiomers of allylic alcohols in high optical purity.8 Furthermore, it has recently been shown that MIB can be used in a one-pot tandem asymmetric addition/diastereoselective epoxidation sequence to generate epoxy alcohols with up to three stereocenters and the asymmetric addition/diastereoselective cyclopropanation with up to four stereogenic centers with high enantio- and diastereoselectivity.9

The distinct advantage of MIB is its ease of preparation. Gram quantities of both enantiomers of MIB can be made in only three steps and one purification, while the most efficient synthesis of (−)-DAIB was achieved in six steps and involved a low yielding and laborious purification step to remove the undesired diastereomer.4 Furthermore, MIB is a crystalline solid and can be stored for months in the presence of air without noticeable decomposition.5

References and Notes

Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104-6323, USA.

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